1,5-benzoxathiepin derivatives

Abstract

Novel 1,5-benzoxathiepin derivatives of the formula: ##STR1## [wherein R 1 and R 2 are independently hydrogen, halogen, hydroxy, lower alkyl or lower alkoxy; R 3 and R 4 are independently hydrogen, optionally substituted lower alkyl or optionally substituted cycloalkyl or optionally substituted aralkyl, or both jointly form an optionally substituted ring together with the adjacent nitrogen atom; X is hydrogen, optionally substituted lower alkyl, optionally substituted aryl or a carboxyl group which may be esterified or amidated; Y is >C═O or >CH--OR 5 (wherein R 5 is hydrogen, acyl or optionally substituted carbamoyl); m is an integer of 0 to 2; n is an integer of 1 to 6] and salts thereof exhibit serotonin S 2 receptor blocking activity, calcium antagonism, actions to relieve cerebral vasospasm and to improve renal circulation and diuretic and antithrombotic activities, and are of value as a prophylactic and therapeutic agent for ischemic cardiopathies, thrombosis, hypertension and cerebral circulatory disorders.

What is claimed is: 
     
       1. A compound of the formula: ##STR65## wherein R 1  and R 2  are independently hydrogen, halogen, hydroxy, C 1-4  alkyl or C 1-4  alkoxy, X is (1) hydrogen, (2) C 1-4  alkyl, (3) C 1-4  alkanoyl, (4) hydroxymethyl, (5) C 1-5  alkanoyloxymethyl, (6) phenyl-C 1-4  alkyl which may be substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy, (7) phenyl which may be substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy, (8) C 1-4  alkoxycarbonyl, (9) phenyl-C 1-4  alkoxycarbonyl, (10) carbamoyl which may be substituted by 1 to 2 members of C 1-4  alkyl, phenyl or phenyl-C 1-4  alkyl or (11) carboxy, and   m is an integer of 0 to 2, or a salt thereof.   
     
     
       2. A compound according to claim 1, wherein R 1  and R 2  are independently hydrogen or C 1-4  alkoxy. 
     
     
       3. A compound according to claim 1, wherein X is hydrogen, carboxy, C 1-4  alkoxycarbonyl, hydroxymethyl or C 1-5  alkanoyl-oxymethyl. 
     
     
       4. A compound according to claim 1, wherein X is C 1-4  alkoxycarbonyl. 
     
     
       5. A compound according to claim 1, wherein m is 0. 
     
     
       6. A compound according to claim 1, wherein R 1  is hydrogen and R 2  is C 1-4  alkoxy. 
     
     
       7. A compound according to claim 1, wherein R 1  is hydrogen, R 2  is C 1-4  alkoxy which is attached at the 7th position of the benzoxathiepin moiety, X is C 1-4  alkoxycarbonyl, and m is 0. 
     
     
       8. A compound according to claim 1, which is methyl 7-methoxy-3-oxo-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate. 
     
     
       9. A compound of the formula: ##STR66## wherein R 1  and R 2  are independently hydrogen, halogen, hydroxy, C 1-4  alkyl or C 1-4  alkoxy. X is (1) hydrogen, (2) C 1-4  alkyl, (3) C 1-4  alkanoyl, (4) hydroxymethyl, (5) C 1-5  alkanoyloxymethyl, (6) phenyl-C 1-4  alkyl which may be substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy, (7) phenyl which may be substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy, (8) C 1-4  alkoxycarbonyl, (9) phenyl-C 1-4  alkoxycarbonyl, (10) carbamoyl which may be substituted by 1 to 2 members of C 1-4  alkyl, phenyl or phenyl-C 1-4  alkyl or (11) carboxy,   Y is C═0 or CH--OR 5   in which R 5  is (i) hydrogen, (ii) C 1-6  alkanoyl, (iii) phenyl C 1-6  alkanoyl unsubstituted or substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy, (iv) carbamoyl unsubstituted or substituted by (1) C 1-4  alkyl, (2) phenyl unsubstituted or substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy or (3) phenyl-C 1-4  alkyl unsubstituted or substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy,     W' is halogen or a group represented by the formula:   R'--SO.sub.2 --O--     wherein     R' is C 1-4  alkyl, phenyl or p-tolyl,   m is an integer of 0 to 2, and   n is an integer of 1 to 6, or a salt thereof.     
     
     
       10. A compound according to claim 9, wherein R 1  and R 2  are independently hydrogen or C 1-4  alkoxy. 
     
     
       11. A compound according to claim 9, wherein X is hydrogen carboxy, C 1-4  alkoxycarbonyl, hydroxymethyl or C 1-5  alkanoyloxymethyl. 
     
     
       12. A compound according to claim 9, wherein X is C 1-4  alkoxycarbonyl. 
     
     
       13. A compound according to claim 9, wherein Y is C═0 or CH--OR 5  in which R 5  is (i) hydrogen, (ii) C 1-6  alkanoyl or (iii) carbamoyl unsubstituted or substituted by (1) C 1-4  alkyl, (2) phenyl unsubstituted or substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino, nitro or hydroxy or (3) phenyl-C 1-4  alkyl unsubstituted or substituted by 1 to 3 members of halogen, C 1-4  alkyl, C 1-4  alkoxy, methylenedioxy, amino nitro or hydroxy. 
     
     
       14. A compound according to claim 9, wherein Y is hydroxymethylene. 
     
     
       15. A compound according to claim 9, wherein m is 0. 
     
     
       16. A compound according to claim 9, wherein n is an integer of 2 to 6. 
     
     
       17. A compound according to claim 9, wherein n is 3. 
     
     
       18. A compound according to claim 9, wherein R 1  is hydrogen and R 2  is C 1-4  alkoxy. 
     
     
       19. A compound according to claim 9, wherein R 1  is hydrogen, R 2  is C 1-4  alkoxy which is attached at the 7th position of the benzoxathiepin moiety, X is C 1-4  alkoxycarbonyl, Y is hydroxymethylene, m is 0, n is 3 and W' is halogen. 
     
     
       20. A compound according to claim 9, which is methyl cis-4-(3-chloropropyl)-3-hydroxy-7-methyoxy-3,4-dihydro-2H-1,5-benzoxathiepin-4-carboxylate.